The data collected in the recent years concerning the primary structure of thyroglobulin (Tg) and the organization of the corresponding gene will be exploited to approach problems of pathological, evolutionary and regulatory significance. The emphasis will be placed mainly on the study of how Tg gene transcription is regulated by thyrotropin (TSH) and cAMP. This research program represents the logical continuation of past efforts. 1. Study of the control of Tg gene transcription Transfection of gene constructs containing the Tg promoter regions upstream from the chloramphenicol acetyl transferase gene will be performed in thyrocytes and nonthyroid cells with the following aims: 1.1. Precise identification of sequences acting as target for cAMP-dependent regulation of transcription. 1.2. Identification of sequences involved in the tissue specific expression of the Tg gene. 1.3. Characterization of factors interacting with the regulatory sequences defined hereabove. 2. Study of the evolution of the Tg gene The sequence organization of non-mammalian Tg will be investigated to test the validity of evolutionary models derived from available structural data. 3. Identification in Tg structure of epitopes involved in thyroid auto-immunity A lambda gtII expression library containing human thyroid cDNA will be screened with hetero- and auto-antibodies with the aim to define the characteristics of Tg sequences involved in the auto-immune process of Hashimoto's thyroiditis. The hypothesis will be tested that the sequence homology between Tg and acetylcholinesterase plays a role in the eitopathogeny of Grave's ophtalmopathy. 4. Study of human goitres with a genetic background 4.1. Restriction fragment length polymorphism at the Tg locus will be used to test the hypothesis that plain goitre with familial clustering would correspond to the heterozygous state of congenital hypothyroidism with Tg gene defect. 4.2. Congenital goitre with Tg deficiency will be investigated using a standardized strategy aiming at the identification of the mutation.